Phelan-McDermid Syndrome and SHANK3: Implications for Treatment

Abstract

Phelan-McDermid syndrome (PMS), also called 22q13.3 deletion syndrome, is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, severe speech delays, poor motor tone and function, and autism spectrum disorder (ASD). Although the overall prevalence of PMS is unknown, there have been at least 1200 cases reported worldwide, according to the Phelan-McDermid Syndrome Foundation. PMS is now considered to be a relatively common cause of ASD and intellectual disability, accounting for between 0.5% and 2.0% of cases. The cause of PMS has been isolated to loss of function of one copy of SHANK3, which codes for a master scaffolding protein found in the postsynaptic density of excitatory synapses. Reduced expression of SH3 and multiple ankyrin repeat domains 3 (SHANK3) leads to reduced numbers of dendrites, and impaired synaptic transmission and plasticity. Recent mouse and human neuronal models of PMS have led to important opportunities to develop novel therapeutics, and at least 2 clinical trials are underway, one in the USA, and one in the Netherlands. The SHANK3 pathway may also be relevant to other forms of ASD, and many of the single-gene causes of ASD identified to date appear to converge on several common molecular pathways that underlie synaptic neurotransmission. As a result, treatments developed for PMS may also affect other forms of ASD.

Fig. 1

Chromosome 22. Schematic representation of the short (p) and long (q) arms of chromosome 22, along with mapped areas of particular interest. The genes located in area 22q13.3, ARSA, SHANK3, ACR, and RABL2B, are represented in a linear fashion, along with their respective sizes [102]

Fig. 2

SH3 and multiple ankyrin repeat domains 3 (SHANK3) protein domains. Schematic representation of the multiple protein domains available for interaction with other proteins [7, 21]. ANK = ankyrin repeat domain; SH3 = Src homology 3; PDZ = PSD-95-discs large-zone occludens-1; Pro-rich = proline-rich region; SAM = sterile alpha motif

Fig. 3

Glutamatergic synapse. Protein binding in the glutamatergic synapse important for synapse structure and function. The ankyrin repeat domain (ANK) binds to α-fodrin and sharpin to form the actin-based cytoskeleton and promote dendritic spine formation [103, 104]. The Src homology 3 (SH3) domain binds to glutamate receptor interacting protein 1 (GRIP1) in order to aid in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking [105, 106]. N-methyl-D-aspartate (NMDA) receptor formation and functioning are mediated by guanylate kinase-associated protein (GKAP)/postsynaptic density protein 95 (PSD-95) binding to the PDZ domain of SH3 and multiple ankyrin repeat domains 3 (SHANK3) [6, 7, 23]. The proline-rich domain of SHANK3 binds Homer1, which mediates metabolic glutamatergic receptor (mGluR) anchoring/functioning [33, 107, 108], and Cortactin, which binds to the neuronal actin cytoskeleton [7]. The sterile alpha motif (SAM) domain binds to other SHANK3 SAM domains to aid in synaptic targeting and self-multimerization [109, 110]. SAP90 = synapse-associated protein 90